Lung cancer is the second most common cancer and has been attributed primarily to cigarette smoking. Other factors contributing to the development of lung cancer include occupational exposure, genetic factors, radon exposure, exposure to other aero-pollutants and possibly dietary factors (Alberg, A. J. et al. Epidemiology of lung cancer. Chest 123:21s-49s, (2003), herein incorporated by reference in its entirety). Non-smokers are estimated to have a one in 400 risk of lung cancer (0.25%). Smoking increases this risk by approximately 40 fold, such that smokers have a one in 10 risk of lung cancer (10%) and in long-term smokers the life-time risk of lung cancer has been reported to be as high 10-15% (Schwartz, A. G. Genetic predisposition to lung cancer. Chest 125:86s-89s, (2004), herein incorporated by reference in its entirety). Genetic factors are thought to play some part as evidenced by a weak familial tendency (among smokers) and the fact that only the minority of smokers get lung cancer. It is generally accepted that the majority of this genetic tendency comes from low penetrant high frequency polymorphisms, that is, polymorphisms which are common in the general population that in context of chronic smoking exposure contribute collectively to cancer development (Schwartz, A G. 2004; Wu, X. et al. Genetic susceptibility to tobacco-related cancer. Oncogene 23:6500-6523, (2004), each of the foregoing which is incorporated by reference in its entirety). Several epidemiological studies have reported that impaired lung function (Anthonisen, N. R. Prognosis in COPD: Results from multi-center clinical trials. Am Rev Respir Dis 140:s95-s99, (1989); Skillrud, D. M. et al. Higher risk of lung cancer in COPD: A prospective matched controlled study. Ann Int Med 105:503-507, (1986); Tockman, M. S. et al. Airways obstruction and the risk for lung cancer. Ann Int Med 106:512-518, (1987); Kuller, L. H. et al. Relation of forced expiratory volume in one second to lung cancer mortality in the MRFIT. Am J Epidmiol 132:265-274, (1990); Nomura, A. et al. Prospective study of pulmonary function and lung cancer. Am Rev Respir Dis 144:307-311, (1991); each of the foregoin which is incorporated by reference in its entirety) or symptoms of obstructive lung disease (Mayne, S. T. et al. Previous lung disease and risk of lung cancer among men and women nonsmokers. Am J Epidemiol 149:13-20, (1999), herein incorporated by reference in its entirety) are independent risk factors for lung cancer and are possibly more relevant than smoking exposure dose.
Despite advances in the treatment of airways disease, current therapies do not significantly alter the natural history of lung cancer, which can include metastasis and progressive loss of lung function causing respiratory failure and death. Although cessation of smoking can be expected to reduce this decline in lung function, it is probable that if this is not achieved at an early stage, the loss is considerable and symptoms of worsening breathlessness likely cannot be averted. Analogous to the discovery of serum cholesterol and its link to coronary artery disease, there is a need to better understand the factors that contribute to lung cancer so that tests that identify at risk subjects can be developed and that new treatments can be discovered to reduce the adverse effects of lung cancer. The early diagnosis of lung cancer or of a propensity to developing lung cancer enables a broader range of prophylactic or therapeutic treatments to be employed than can be employed in the treatment of late stage lung cancer. Such prophylactic or early therapeutic treatment is also more likely to be successful, achieve remission, improve quality of life, and/or increase lifespan.
To date, a number of biomarkers useful in the diagnosis and assessment of propensity towards developing various pulmonary disorders have been identified. These include, for example, single nucleotide polymorphisms including the following: A-82G in the promoter of the gene encoding human macrophage elastase (MMP12); T→C within codon 10 of the gene encoding transforming growth factor beta (TGFβ); C+760G of the gene encoding superoxide dismutase 3 (SOD3); T-1296C within the promoter of the gene encoding tissue inhibitor of metalloproteinase 3 (TIMP3); and polymorphisms in linkage disequilibrium with these polymorphisms, as disclosed in PCT International Application PCT/NZ02/00106 (published as WO 02/099134 and herein incorporated by reference in its entirety).